scholarly journals 515 A phase 1 study of myeloid modulating agent MTL-CEBPA in combination with pembrolizumab in adult patients with advanced solid tumours

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A545-A545
Author(s):  
Ruth Plummer ◽  
Mikael Sodergren ◽  
David Pinato ◽  
Debashis Sarker ◽  
Vikash Reebye ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Myeloid Cell ◽  
Maximum Tolerated Dose ◽  
Solid Tumours ◽  
Adult Patients ◽  
Clinical Activity ◽  
Open Label ◽  
North East

BackgroundMTL-CEBPA is a novel immunotherapy targeting the myeloid cell lineage which has shown promising clinical activity as monotherapy and combination therapy with tyrosine kinase inhibitors in hepatocellular carcinoma (HCC). Immunosuppressive myeloid cells are associated with worse outcomes to checkpoint inhibitors. Pre-clinical data have shown that MTL-CEBPA potentiates the oncological effect of PD-1 inhibitors.MethodsThis phase 1A/B, first-in-human, open-label, multicenter study evaluates the safety, tolerability, PK, and efficacy of MTL-CEBPA in combination with a pembrolizumab in adult patients with advanced solid tumours across 3 dose cohorts (70mg/98mg/130mg/m2 MTL-CEBPA once weekly for 3 consecutive weeks with final week break per cycle, with 200mg pembrolizumab every 3 weeks). The primary endpoint is safety and ORR; key secondary endpoints include PK, CR rate & DCR. Key inclusion criteria: Patients with advanced solid tumours who have progressed on standard of care therapy or for whom no standard therapy is available, measurable disease, ECOG PS <2, life expectancy >3 months. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D).Results10 pts (3 men, 7 women; median age 50.5yrs), all with different tumor types (1 each of triple negative breast, methothelioma, squamous thymic, cholangiocarcinoma, eccrine, fibrolamellar hepatocellular, colorectal, pancreatic and 2 platinum resistant high-grade serous ovarian). 4 pts had ≥4 prior lines of treatment. All pts reported treatment-related AEs, 7 pts reported AEs considered related to MTL-CEBPA only and all were grade 1 or 2. The most common was nausea (n=3) followed by anaemia, headache, insomnia, neutropenia, pyrexia, transaminase increase and ventricular extrasystole (all n=1). Five pts reported AEs considered related to pembrolizumab only, 2AEs in 1 pt only were grade 3 (ALT and AST increases) There were no DLTs, SAEs or AEs leading to discontinuation or to death in the study. Tumor response was evaluated in 9 pts. 2 pts had a PR (epithelioid mesothelioma at 2 months with 83% tumour reduction, pt ongoing at 9 months & serous ovarian cancer at 2 months with 69% reduction in tumour, pt progressed at 6 months). Three pts had SD, 4 pts had PD as BOR, and 4 pts are continuing to receive treatment.ConclusionsMTL-CEBPA in combination with pembrolizumab demonstrated manageable toxicity at the dose levels tested and has shown antitumor activity. MTD was not reached and RP2D was determined at 130mg/m2 on day 1, 8 and 15 of a 28 day cycle. Enrolment into the dose expansion is ongoing.Trial RegistrationThis study was registered with ClinicalTrials.gov, number NCT04105335.Ethics ApprovalThe study was approved by the North East - Newcastle & North Tyneside 2 Research Ethics Committee, approval number 19/NE/0312.

Phase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, DUR) + tremelimumab (TRE) in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3069-3069 ◽  
Author(s):  
Margaret K. Callahan ◽  
Kunle Odunsi ◽  
Mario Sznol ◽  
John J. Nemunaitis ◽  
Patrick Alexander Ott ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Liver Function Tests ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Tumor Type ◽  
Open Label ◽  
Expansion Phase ◽  
Combination Methods

3069 Background: DUR is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1. TRE is a human IgG2 mAb inhibitor of CTLA-4. Blocking these checkpoints can result in antitumor activity in some solid tumors. The targets for DUR and TRE are non-redundant, providing sound rationale for clinical testing of the combination. Methods: This is an ongoing Phase 1, multicenter, open label study (NCT01975831) with a dose escalation (3+3 design) and subsequent expansion phase. Patients (pts) with renal cell carcinoma (RCC), cervical (CC), colorectal (CRC), non-triple-negative breast (NTNBC), ovarian (OC), non-small cell lung, or head and neck cancer are eligible. Primary endpoints are safety/tolerability and identification of maximum tolerated dose (MTD) of the combination. Secondary objectives include tumor response and progression-free/overall survival. Results: As of 16 Dec 2016, 105 pts were treated. DUR 1500 mg every 4 weeks (Q4W) and TRE 75 mg Q4W X 4 was the regimen used for opening the expansion phase. Dose-limiting toxicities were reported in 4 pts: diarrhea, colitis, abnormal liver function tests (abn LFTs), and hyponatremia. The majority of treatment-related AEs (TRAEs) were Grades (Gr) 1 and 2. TRAEs ≥ Gr 3 were reported in 12 pts; the majority were diarrhea/colitis (n = 5) and abn LFTs (n = 4) and responded to established treatment algorithms. There was 1 Gr 5 TRAE: multi organ failure. No new toxicities were identified. The preliminary responses by tumor type with n ≥ 10 pts are shown in the table below. Responses were seen in OC and RCC at the Cohort 2 dose escalation level (DUR 1/TRE 3 mg/kg). There were 4 cases of SD > 24 weeks: CC, n=2; CRC, n=1; OC, n=1. PD-L1 status was not tested. Conclusions: The DUR + TRE combination has a manageable safety profile, with preliminary evidence of clinical activity. These data support continued study of the combination therapy; the study is ongoing. Clinical trial information: NCT01975831. [Table: see text]

A phase I study of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 408-408
Author(s):  
Costantine Albany ◽  
Michael J. Spinella ◽  
Nabil Adra ◽  
Nasser H. Hanna ◽  
Lawrence Einhorn
Keyword(s):  
Germ Cell ◽  
Phase 1 ◽  
Objective Response ◽  
Germ Cell Tumors ◽  
Maximum Tolerated Dose ◽  
Neutropenic Fever ◽  
Epigenetic Therapy ◽  
Clinical Activity ◽  
Open Label ◽  
Platinum Refractory

408 Background: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Platinum-refractory germ cell tumors (GCT) showed significant DNA hypermethylation compared to platinum sensitive tumors. In preclinical studies, GCT were extremely sensitive to low dose decitabine which restored sensitivity to cisplatin in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT. Methods: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 with growth factor support (GFS) in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of the combination, determine the maximum tolerated dose (MTD). Secondary objective was objective response rate (ORR). Results: Fourteen patients with incurable disease were enrolled. Primary site were testis 11, mediastinum 2, and ovarian 1. All progressed after at least 2 lines of standard of care chemotherapy including HDCT. Dose-limiting toxicities were neutropenic fever. Most common toxicities were neutropenia (82% any grade), thrombocytopenia (42%), anemia (33%), neutropenic fever (8%), and diarrhea (8%). The maximum tolerated dose of guadecitabine was 30 mg/m2 x 5 days and cisplatin 100 mg/m2. We observed 2/14 complete response lasting more than 6 months, 2 partial response and 1 stable disease. ORR 28.5%. Conclusions: We report the first study of chemo-priming with epigenetic therapy in GCT. Guadecitabine 30 mg/m2 x 5 days and cisplatin 100 mg/m2 with GFS was safe and tolerable and showed promising activity with 4/14 responses in this highly treatment refractory patient population. Clinical trial information: NCT02429466.

scholarly journals Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia

2019 ◽  
Vol 3 (13) ◽  
pp. 1939-1949 ◽  
Author(s):  
Harry P. Erba ◽  
Pamela S. Becker ◽  
Paul J. Shami ◽  
Michael R. Grunwald ◽  
Donna L. Flesher ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Refractory Acute Myeloid Leukemia ◽  
Higher Doses ◽  
Acute Myeloid

AbstractThis open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX, PUMA, P21, and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53-wild-type patients and 0 of 3 (0%) TP53-mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at www.clinicaltrials.gov as #NCT02016729.

Replacement of ixazomib for relapsed/refractory multiple myeloma patients refractory to a bortezomib or carfilzomib-containing combination therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8013-8013 ◽  
Author(s):  
James R. Berenson ◽  
Alexa Cohen ◽  
Tanya M. Spektor ◽  
Jacob D. Bitran ◽  
Gigi Qiqi Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
The Other ◽  
Clinical Activity ◽  
Combination Regimen ◽  
Open Label ◽  
Combination Regimens

8013 Background: The proteasome inhibitor (PI) ixazomib (Ixz) is the first orally administered PI approved for treating multiple myeloma (MM). It has shown clinical activity as a single agent and when used in other combinations. In this phase 1/2 trial, we evaluated Ixz as a replacement therapy for bortezomib or carfilzomib for MM patients who were refractory to a bortezomib- or carfilzomib-containing combination regimen. Methods: This was a phase 1/2, intra-patient, multicenter, open-label trial evaluating the replacement of ixazomib for bortezomib or carfilzomib for MM patients who were refractory in combination with the other agents that the patients had received and failed. Patients received Ixz on days 1, 8 and 15 on a 28-day schedule and the other drugs were administered using the same doses and schedules as they were receiving during their prior regimen. If the Ixz maximum tolerated dose (MTD) for a particular combination regimen was previously determined, then patients were enrolled directly into Phase 2 (PhII). If not, MTD was determined during the Phase 1 (PhI) portion of the trial. Results: To date, a total of 40 patients have been enrolled; 37 patients (21 were enrolled in PhI and 16 in PhII) had completed at least one cycle of this treatment. Patients received a median of 5 prior treatments (range, 1-22). The median follow-up time for all patients was 1.6 months (range, 0.1-10.7 months), whereas that of PhII was 2.2 months (range, 0.2-10.7 months). There was no clinical benefit (CBR; 0%) nor any overall response rate (ORR; 0%) for patients receiving Ixz 3 mg (PhI). Nine patients (43%) showed stable disease (SD) while 12 (57%) exhibited disease progression (PD). In PhII (4mg Ixz) portion of the trial, ORR and CBR were both 18.7% with 16 (43.2%) patients showing SD, and 18 (48.6%) patients displaying PD. Common ≥ Gr3 adverse events were anemia (11%), thrombocytopenia (5.4%), hyponatremia (5.4%), dehydration (5.4%) and neutropenia (2.7%). Conclusions: Replacement of bortezomib or carfilzomib with Ixz infrequently leads to responses among RRMM patient who have progressed while on proteasome inhibitor -containing combination regimens. Clinical trial information: NCT02206425.

Escalation portion of phase II study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K/mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2550-2550
Author(s):  
Patrick Y. Wen ◽  
John Frederick De Groot ◽  
James D. Battiste ◽  
Samuel Aaron Goldlust ◽  
James Stuart Garner ◽  
...  
Keyword(s):  
Oral Mucositis ◽  
Dose Escalation ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Current Phase ◽  
Clinical Activity ◽  
High Grade ◽  
Newly Diagnosed ◽  
Open Label ◽  
Once Daily

2550 Background: Paxalisib (previously GDC-0084) is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. The PI3K pathway is upregulated in ~85% of GBM cases and paxalisib has shown efficacy in preclinical models. A phase I study (NCT01547546) investigated paxalisib dosed once daily in 47 patients with recurrent high-grade gliomas and established a maximum tolerated dose (MTD) of 45mg once daily. The current phase Il study aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Methods: Part 1 of this study is an open-label, dose-escalation phase to assess the safety, tolerability and MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 is an expansion cohort recruiting 20 patients randomized to administration in fed or fasted states at the MTD. Results: Part 1 is complete and reported here. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis. AEs were generally reversible and consistent with the PI3K inhibitor class with the most common events were rash, oral mucositis, and fatigue. PK at the MTD was broadly consistent with the data published for the phase 1 study. For eight response-evaluable patients in Part I the median progression-free survival (PFS) was 8.4 months, and 25% of patients remained progression free after 15 months of follow-up. Part 2 is ongoing. Conclusions: A higher MTD of 60mg was identified in newly diagnosed GBM with unmethylated MGMT promotor status than the 45mg MTD previously identified in recurrent high-grade glioma. An encouraging PFS signal is described in this poor-prognosis, unmethylated MGMT patient population. Clinical trial information: NCT03522298 .

Phase I study of everolimus in combination with fluvastatin and zoledronic acid in patients with solid tumours.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13585-e13585
Author(s):  
Charlotte Rose Lemech ◽  
Antoinette Fontela ◽  
Hendrik-Tobias Arkenau ◽  
Melvin T.M. Chin ◽  
Sandra Li ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Phase I ◽  
Phase 1 ◽  
Median Number ◽  
Solid Tumours ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Open Label ◽  
Post Dose ◽  
Best Response

e13585 Background: Everolimus (E) is an mTOR inhibitor with broad anti-tumour clinical activity. There is preclinical evidence of synergistic activity through the combination of E with fluvastatin (F) and zoledronic acid (ZA). F, an HMG CoA reductase inhibitor, and ZA, a bisphosphonate, have both been shown preclinically to inhibit isoprenylation (addition of hydrophobic molecules) of key signalling proteins with subsequent inhibition of the Ras pathway. We investigate their potential activity further in this open-label phase I trial. Methods: Patients (pts) with advanced solid tumours were treated with escalating doses of E, F and ZA to evaluate safety, clinical activity, pharmacokinetics (PK), pharmacodynamics (PD) and the recommended dose for further study. PK samples were obtained over 24 hrs on day 1 and 8 of cycle 1 and day 1 of cycle 2. Pre- and post-dose PBMCs were analysed for markers of MAPK and PI3K-AKT-mTOR pathways (pERK, pAKT and pS6). Results: Maximum doses of each drug in combination (DL 4) were feasible and no DLTs were observed. Of the 16 pts evaluable [median age=63yrs (range 47-81)], the median number of cycles was 3.8 (range 1-8), with 44% of pts receiving ≥ 4 cycles. Drug related toxicities were mainly G1/2, many within the expected toxicity profile of E, including fatigue (12 pts, 75%), myalgias (9 pts, 56%), anorexia (8 pts, 50%), infection (8pts, 50%), dyspnoea (7pts, 44%), diarrhoea (7 pts, 44%), nausea (7 pts, 44%), peripheral oedema (5 pts, 31%) and mucositis (4 pts, 25%). G3 adverse events were predominantly due to symptoms of disease progression. G1/2 anemia and thrombocytopaenia were the most common haematological toxicities, particularly in DL 3 and 4. 44% of pts achieved stable disease as best response (mean 4.5m [range 3-6m]); including 2 CRC pts (DL 4) and 2 CRPC pts (DL 3 and 4). PK and PD results will be presented in further detail. Conclusions: The combination of E/F/ZA is feasible without any added or overlapping toxicities in this phase 1 study. [Table: see text]

A phase 2 trial of CRS-207 and pembrolizumab in adults with recurrence of metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinomas.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS200-TPS200
Author(s):  
Ronan Joseph Kelly ◽  
Thomas Adam Abrams ◽  
Daniel V.T. Catenacci ◽  
Zev A. Wainberg ◽  
Bruce Shih-Li Lin ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Clinical Activity ◽  
Cell Mediated Immunity ◽  
Specific Cell ◽  
Phase 2 ◽  
Open Label ◽  
Mesothelin Expression

TPS200 Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) strain with a mesothelin expression cassette inserted. CRS-207 has a well-established, manageable toxicity profile and can elicit mesothelin-specific cell-mediated immunity. Clinical activity of CRS-207 has been shown in a separate Phase 1 trial of mesothelioma. In gastroesophageal (GE) cancers, mesothelin expression is estimated between 30% – 50% and has been correlated with poor prognosis. Preclinical models suggest the combination of LADD-based immunotherapeutics and a PD1 inhibitor may induce more sustained anti-tumor responses than either LADD or PD1 inhibitor monotherapy. GE cancers are responsive to PD1 inhibitors in a subset of patients; this trial proposes to evaluate the efficacy of CRS-207 combined with pembrolizumab in patients with relapsed GE cancer, and to correlate clinical activity with mesothelin expression level. Methods: This Phase 2, open-label, single-arm, multicenter clinical study (NCT 03122548) will enroll approximately 79 subjects at 20 sites. Adults with histologically-confirmed, advanced gastric, GEJ, or esophageal adenocarcinomas are eligible. Subjects must have received 1 or 2 prior treatment regimens, which must have included a platinum and a fluoropyrimidine. Subjects must have disease progression with measurable tumors. A pre-treatment biopsy of either the primary tumor or metastatic site is required prior to dosing. Subjects with prior exposure to checkpoint inhibitors or other immunotherapies are excluded. From cycle 1 to 4 during the treatment and evaluation period, pembrolizumab (IV 200 mg) and CRS-207 (IV 1 x 109 CFU) are both administered in 3-week cycles. Afterward, pembrolizumab will be administered once every 3 weeks; CRS-207 will be given once every 6 weeks. CT scans will be performed every 6 weeks to monitor disease status. The primary endpoint is objective response rate defined by RECIST 1.1. Clinical trial information: NCT03122548.

scholarly journals A Dose-Escalation (DE) Study with Expansion Evaluating Safety, Pharmacokinetics and Efficacy of the Novel, Balanced PI3K/mTOR Inhibitor PQR309 in Patients with Relapsed or Refractory Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5893-5893 ◽  
Author(s):  
Graham P. Collins ◽  
Rakesh Popat ◽  
Anastasios Stathis ◽  
Fatime Krasniqi ◽  
Toby A. Eyre ◽  
...  
Keyword(s):  
Phase 1 ◽  
Solid Tumours ◽  
Dose Finding ◽  
Clinical Activity ◽  
Open Label ◽  
Mtor Inhibition ◽  
Dosing Schedule ◽  
Systemic Treatments ◽  
Refractory Lymphoma

Abstract Background:PQR309 is an oral balanced, pan-PI3K, mTORC1 and mTORC2 inhibitor. It is in clinical development for the treatment of solid tumors and hematologic malignancies. 1st generation mTOR inhibitors inhibit the activity of mTOR within the TORC1 complex only with activation of TORC2 proposed as a putative resistance mechanism. PI3 kinase inhibition may reduce subsequent AKT activation which can bypass some effects of mTOR inhibition. Potent antiproliferative activity of PQR309 was previously demonstrated in lymphoma cell lines in vitro and in vivo. Maximum tolerated dose (MTD) of PQR309 in solid tumours was established at 80 mg using a continuous once daily dosing schedule (OD). Methods:We performeda modified 3+3 DE of PQR309, open label phase 1 trial with expansion, to evaluate safety, pharmacokinetics (PK) and efficacy. Patients with relapsed or refractory lymphoma (any sub-type, ECOG PS of 0-1) were treated in two sequential cohorts with escalating doses of PQR309 administered on an OD dosing schedule to assess the MTD of PQR309. The starting dose of PQR309 was 60mg OD. The dose limiting toxicity (DLT) period was the first cycle of treatment, 21 days (d). PK samples were obtained at predefined time points. Clinical efficacy was evaluated according to revised Cheson criteria. In the expansion phase, patients will be treated at the MTD as defined in the DE phase of the study. Results: 15 patients were enrolled between August 2015 and March 2016 and treated with 60mg (n=8) or 80mg (n=7) of PQR309. Demographics: 5F:10M; median age 60 (range: 34-75), median number of prior systemic treatments 5 (range: 1-8). Lymphoma indications are shown in Table 1. Mean duration on therapy was 39 days (range: 3-160). One patient with follicular lymphoma remains on treatment. Grade (G)3/4 drug-related AE were seen in 3 patients treated with 60mg: 1 G4 rhabdomyolysis, 1 G4 neutropenia, 1 G3 hyperglycemia and one patient who developed G3 anorexia and G4 sepsis. Four patients treated with 80mg developed G3/4 drug-related AEs: two patients developed G3 hyperglycemia, one patient developed G3 fatigue and G3 pneumonitis. No DLT was observed. Preliminary PK showed rapid absorption (Tmax 1-2h), dose proportionality for Cmax and AUC and an estimated T1/2 of around 50 hours, consistent with PQR309 studies in solid tumours that evaluated dose levels from 10 to 150 mg PQR309. Responses observed in each patient are shown in the table below. 4 patients were non-evaluable, 3 due to disease progression requiring cessation of study drug and one requiring steroid doses exceeding protocol defined criteria, all within the 21 day DLT assessment period. Conclusion:The MTD and recommended PQR309 dose for the expansion of the study was 80mg OD, in agreement with earlier dose-finding studies in solid tumours. Adverse event patterns were consistent with those seen in studies involing solid tumours. Hyperglycemia, a predicted on-target effect of PI3K/mTOR inhibition, was observed in the majority of patients, providing evidence of pharmacodynamic effects of PQR309. PK was dose-proportional. Encouraging clinical activity including a CR was observed. The study expansion is ongoing. Disclosures Collins: Takeda: Consultancy, Honoraria, Speakers Bureau. Eyre:GSK: Honoraria; Celgene: Other: Travel, Accomodation; Gilead: Honoraria, Other: Travel, Accomodation, Speakers Bureau; Takeda: Honoraria, Other: Travel, Speakers Bureau. Ivanova:PIQUR: Employment. Schmitz:PIQUR: Employment. Dimitrijevic:PIQUR: Employment. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Safety and tolerability of MEDI0562 in combination with durvalumab or tremelimumab in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3003-3003
Author(s):  
Jonathan Wade Goldman ◽  
Sarina Anne Piha-Paul ◽  
Brendan D. Curti ◽  
Katrina Pedersen ◽  
Todd Michael Bauer ◽  
...  
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Memory T Cells ◽  
Phase 1 ◽  
Evaluation Criteria ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
The Impact

3003 Background: We report safety and tolerability of MEDI0562, a humanized IgG1κ OX40 monoclonal antibody (mAb), in combination with durvalumab (durva; anti-PD-L1 mAb) or tremelimumab (treme; anti-CTLA-4 mAb) in patients (pts) with previously treated advanced solid tumors. Methods: In this phase 1, open-label study (NCT02705482), adult pts received escalating doses of MEDI0562 (2.25, 7.5 or 22.5 mg/kg) every 2 wks (Q2W) in combination with durva (1500 mg/kg) or treme (75 or 225 mg/kg) Q4W, until confirmed disease progression or unacceptable toxicity. Tumor assessments were performed Q8W with immune-related Response Evaluation Criteria in Solid Tumors. Results: In total, 27 and 31 pts received MEDI0562 + durva or treme, across 5 dose combination cohorts (3 + 3 design), with a maximum tolerated dose of 7.5 mg MEDI0652 + 1500 mg durva and maximum administered dose of 10 mg MEDI0562 + 225 mg treme. Median duration of exposure was 12.0 (range 2.0–80.9) and 8.0 (range 2.0–42.0) wks, respectively. Two (22.5 mg MEDI10562 + durva) and 3 (2.25 mg MEDI0652 + 225 mg treme, 22.5 mg MEDI0562 + 75 and 225 mg treme) dose limiting toxicities were observed. For MEDI0562 + durva and MEDI0562 + treme groups respectively, treatment-emergent adverse events (TEAEs) were reported in 96.3% and 100% of pts; most common TEAEs were fatigue (55.6%) and pruritus (45.2%), Gr 3/4 TEAEs occurred in 74.1% and 67.7%; and MEDI0562-related AEs were reported in 20 (74.1%) and 24 (77.4%) pts. Six TEAEs in each group led to MEDI0562 discontinuation (22.2% and 19.4%, respectively), 2 led to death (renal failure [7.5 mg MEDI0562 + durva], multiple organ dysfunction syndrome [22.5 mg MEDI0562 + 225 mg treme]). Three response evaluable pts had PR (11.5% [7.5 and 22.5 mg MEDI0562 + durva, n = 26]). Median overall survival was 17.4 and 11.9 mos for MEDI0562 + durva and MEDI0562 + treme, with stable disease seen in 9 pts from each group, 34.6% vs 29.0%, respectively. Serum exposure of MEDI0562 increased dose proportionally. Post treatment serum antidrug antibody (ADA) was detected in 20 pts from MEDI0562 + durva and MEDI0562 + treme (74.1% and 71.4%, respectively). The impact of ADA on MEDI0562 pharmacokinetics was seen at all doses. Mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased, while mean percentage of OX40+CD4+ memory T cells decreased following the first dose of MEDI0562 + durva or treme. Conclusions: The safety profile of MEDI0562 in combination with durva or treme was similar between groups. Clinical activity was observed with MEDI0562 + durva in pts with advanced solid tumors. Clinical trial information: NCT02705482 .

A phase I study evaluating COM701 in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2657-TPS2657
Author(s):  
Drew W. Rasco ◽  
Daniel A. Vaena ◽  
Ryan J. Sullivan ◽  
Jason J. Luke ◽  
Adam ElNaggar ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Locally Advanced ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Mouse Tumor ◽  
Advanced Solid Tumors ◽  
Open Label

TPS2657 Background: There is a high unmet medical need for the treatment (tx) of patients (pt) who are refractory to or relapse following tx with checkpoint inhibitors. Newer checkpoint therapies with novel mechanisms of action that can activate T cells and demonstrate antitumor activity in this pre-tx pt population are urgently needed. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to PVRIG (poliovirus receptor related immunoglobulin domain containing) blocking its interaction with its ligand, PVRL2. Both PVRIG and PVRL2 are part of the DNAM axis as are TIGIT and PD1. Inhibition of PVRIG leads to enhanced activation of T and NK cells, and PVRIG results in tumor growth inhibition in mouse tumor models. We hypothesize that COM701 will demonstrate antitumor activity in pts who are checkpoint inhibitor pre-tx. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with advanced solid tumors. The initial part of this study (Arm A) will evaluate escalating doses of COM701 monotherapy IV Q3 weekly with single pt cohorts for the initial 4 and then 3+3 design. Key Inclusion Criteria: Age ≥18 yrs, histologically confirmed locally advanced/ metastatic solid malignancy and has exhausted available standard therapy, ECOG 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137 permissible. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years, symptomatic interstitial or inflammatory lung disease, untx or symptomatic central nervous system metastases. Primary objectives are safety and tolerability of COM701 as measured by the incidence of adverse events (AEs) and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701, and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary objectives are to characterize the immunogenicity and preliminary antitumor activity of COM701. Statistical Considerations: AEs graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. No DLTs have been observed in the single pt cohorts. Assessment of pts enrolled into cohort 5 is ongoing at the time of this submission. Clinical trial information: NCT03667716.

Sign in / Sign up

Export Citation Format

Share Document